Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.

Autor:	Mamais A; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America.; Department of Neurology, University of Florida, Gainesville, Florida, United States of America., Kluss JH; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Bonet-Ponce L; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Landeck N; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Langston RG; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Smith N; Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska, United States of America., Beilina A; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Kaganovich A; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Ghosh MC; Molecular Medicine Branch, 'Eunice Kennedy Shriver' National Institute of Child Health and Human Development, Bethesda, Maryland, United States of America., Pellegrini L; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Kumaran R; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Papazoglou I; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America., Heaton GR; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America., Bandopadhyay R; UCL Institute of Neurology and Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom., Maio N; Molecular Medicine Branch, 'Eunice Kennedy Shriver' National Institute of Child Health and Human Development, Bethesda, Maryland, United States of America., Kim C; Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., LaVoie MJ; Department of Neurology, University of Florida, Gainesville, Florida, United States of America., Gershlick DC; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom., Cookson MR; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Maryland, United States of America.
Jazyk:	angličtina
Zdroj:	PLoS biology [PLoS Biol] 2021 Dec 16; Vol. 19 (12), pp. e3001480. Date of Electronic Publication: 2021 Dec 16 (Print Publication: 2021).
DOI:	10.1371/journal.pbio.3001480
Abstrakt:	Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia. Competing Interests: The authors have declared that no competing interests exist.
Databáze:	MEDLINE
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